Mechanisms of action of drugs that prevent experimental diabetic retinopathy

描述（由申请人提供）：我们工作的最终目标是开发预防糖尿病视网膜病变的药物策略。随着强化血糖控制的逐步广泛实施，预防已经成为可能，我们预计，在预先消除残余高血糖对组织的影响方面有效且长期服用安全的药物的加入，将使预防成为现实。目前还没有临床可用的辅助药物，也没有关于哪种药物可能有效预防人类糖尿病视网膜病变的严格阳性或阴性信息。因此，我们试图从预防实验性糖尿病视网膜病变的药物中了解到，为了防止糖尿病引起的视力威胁损伤，视网膜血管中的分子过程必须被沉默。我们测试了两种具有不同作用机制的药物（醛糖还原酶抑制剂和中低浓度阿司匹林），理由是这两种药物共同的分子靶标将确定候选的致病途径，以便进一步研究。实验表明，在大鼠中，(i)糖尿病改变视网膜血管中多个基因的表达；（ii） tgf - β途径是受糖尿病影响最大的单一功能途径；（iii）两种药物既有各自的靶点，也有共同的靶点，tgf - β途径是两个共同的功能靶点之一。鉴于tgf - β通路的过度活性可以解释糖尿病视网膜病变的大部分血管组织病理学，并且基于记录糖尿病视网膜血管中tgf - β信号增加的额外结果，我们计划验证过量tgf - β信号有助于糖尿病视网膜病变特征性血管病理学的假设。该项目尤其令人兴奋的是，有机会使用一种名为SM16的新型tgf - β I型受体激酶小分子抑制剂，它具有口服活性，是翻译步骤中最吸引人的特征。我们的目标是在糖尿病大鼠中开发和验证基于SM16的药物策略，用于非侵入性，长期和靶向预防视网膜血管中过量的tgf - β信号。精确的目标是在不降低基础tgf - β活性的情况下使tgf - β信号恢复到控制值。我们将使用该抑制剂来了解过量tgf - β信号在糖尿病视网膜血管中的分子效应。然后，我们将测试通过消除这些影响，视网膜毛细血管是否能免受细胞死亡和重塑的影响，而细胞死亡和重塑最终会导致糖尿病的死亡。在相同的大鼠中，我们还将研究SM16对典型肾脏病理发展的影响。最后，我们将研究人类糖尿病视网膜血管（死后眼睛）中的tgf - β通路。临床前研究和人类糖尿病视网膜的积极结果将确定过量的tgf - β信号是糖尿病视网膜病变血管病理的一个因素，并将刺激药物的研究和开发，以安全调节人类tgf - β活性。此外，这些研究准备为抗tgf - β治疗在其他病理中的应用提供一个范例。

DESCRIPTION (provided by applicant): The ultimate goal of our work is to develop drug strategies for the prevention of diabetic retinopathy. Prevention has been brought within reach by the progressively wider implementation of intensive glycemic control, and we anticipate that the addition of drugs that are effective in pre-emptying the tissue effects of residual hyperglycemia and are safe for long-term administration will make prevention a reality. There are no adjunct drugs usable clinically, and there are no rigorous positive or negative information on the type of drugs that may be effective in the prevention of human diabetic retinopathy. We thus sought to learn from drugs that prevent experimental diabetic retinopathy which molecular processes must be silenced in the retinal vessels in order to prevent the sight-threatening damage induced by diabetes. We tested two drugs with different mechanisms of action (an aldose reductase inhibitor and aspirin at low-intermediate concentrations) reasoning that molecular targets common to the two drugs would identify candidate pathogenic pathways to be investigated further. The experiments showed that, in rats, (i) diabetes changes the expression of multiple genes in retinal vessels, (ii) the TGF-beta pathway was the single functional pathway mostly affected by diabetes, and (iii) the two drugs had private as well as common targets, with the TGF-beta pathway being one of the two common functional targets. Given that overactivity of the TGF-beta pathway could explain much of the vascular histopathology of diabetic retinopathy, and based on additional results documenting increased TGF-beta signaling in diabetic retinal vessels, we plan to test the hypothesis that excess TGF-beta signaling contributes to the characteristic vascular pathology of diabetic retinopathy. The project is made especially exciting by the opportunity to use a new small molecule inhibitor of TGF-beta type I receptor kinase, named SM16, that is orally active, a most appealing feature for translational steps. We aim to develop and validate in diabetic rats a drug strategy based on SM16 for non-invasive, long-term, and on-target prevention of the excess TGF-beta signaling in retinal vessels. The precise aim is to bring TGF-beta signaling back to control values without reducing basal TGF-beta activity. We will use the inhibitor to learn the molecular effects of excess TGF-beta signaling on diabetic retinal vessels. We will then test whether by taking away such effects, the retinal capillaries are protected from the cell death and remodeling that lead to their final demise in diabetes. In the same rats we will also examine the effects of SM16 on the development of the typical renal pathology. Finally, we will examine the TGF-beta pathway in human diabetic retinal vessels (postmortem eyes). A combination of positive results in the preclinical studies and the human diabetic retina will identify excess TGF-beta signaling as a contributor to the vascular pathology of diabetic retinopathy and will stimulate investigation and development of drugs to modulate safely TGF-beta activity in humans. In addition, the studies are poised to generate a paradigm for applications of anti-TGF-beta therapy to other pathologies.